1. Field of the Invention
This invention is directed to novel substituted 3-indolyl-5-pyrazolone compounds as well as intermediates useful in the preparation of such substituted 3-indolyl-5-pyrazolone compounds. This invention is also directed to methods for the use of such substituted 3-indolyl-5-pyrazolone compounds.
2. References
The following publications and patent application are cited in this application as superscript numbers at the relevant portion of the application:
.sup.1 Schenk, et al., International Patent Application Publication No. WO 94/10569, "Methods and Compositions for the Detection of Soluble .beta.-Amyloid Peptide", published 11 May 1994 PA0 .sup.2 Selkoe, Scientific American, "Amyloid Protein and Alzheimer's Disease", pp. 2-8, November, 1991 PA0 .sup.3 Mansour and Evans, Synth. Commun., "Decarboxylative Carbon Acylation of Malonates with Aminoacylimidazolides Mediated by Lewis Acids", 20(5):773-781 (1990) PA0 .sup.4 Wierenga and Skulnick, J. Org. Chem., "General, Efficient, One-Step Synthesis of .beta.-Keto Esters", 44:310-311 (1979) PA0 .sup.5 Ghali, et al., J. Org. Chem., "A High-Yielding Synthesis of Monoalkylhydrazines", 46:5413-5414 (1981) PA0 .sup.6 Coleman, Organic Synthesis, "Phenylhydrazine", Coll. Vol. 1, pp. 442-445 PA0 .sup.7 Yamamoto, et al., Chem. Pharm. Bull., "I-Acylindoles. IV. Novel Syntheses of 1-Benzoylindole-3-aliphatic Acids", 16(4):647-653 (1968) PA0 .sup.8 Shen, U.S. Pat. No. 3,190,889, "1-Substituted-3-Indolyl Aliphatic Acids", issued Jun. 22, 1965 PA0 .sup.9 Sarett, et al., U.S. Pat. No. 3,242,162, "Indolyl Aliphatic Acids", issued Mar. 22, 1966 PA0 .sup.10 Shen, U.S. Pat. No. 3,201,414, "New 1-Heteroacyl-3-Indolyl Aliphatic Acids", issued Aug. 17, 1965 PA0 .sup.11 Shen, U.S. Pat. No. 3,161,654, ".alpha.-(1-Aroyl-3-Indolyl)Alkanoic Acids", issued Dec. 15, 1964 PA0 .sup.12 Glenner, et al., "Polypeptide Marker for Alzheimer' Disease and its Use ofr Diagnosis", U.S. Pat. No. 4,666,829, issued May 19, 1987 PA0 .sup.13 Wiley and Wiley, The Chemistry of Heterocyclic Compounds, Vol. 20, Interscience, New York, N.Y. (1964) PA0 .sup.14 Hutchinson, et al., Ann. Rev. Biochemistry, 63:383-417 (1994) PA0 .sup.15 Baran, et al., Brain Research, The Cyclooxgenase and Lipoxygenase Inhibitor BW755C Protects Rats Against Kainic Acid-Induced Seizures and Neurotoxicity", 646:201-206 (1994) PA0 .sup.16 Citron, et al., Nature, 360:672-674 (1992) PA0 .sup.17 Hansen, et al., J. Immun. Meth., 119:203-210 (1989) PA0 .sup.18 Shimuzu, et al., Enzyme with Dual Lipoxygenase Activities Catalyzes Leukotriene A4 Synthetase from Arachidonic Acid, Proc. Natl. Acad. Sci. USA, 81:689-693 (1984) PA0 .sup.19 Egan, et al., Inhibition of Mammalian 5-Lipoxygenase by Aromatic Disulfides, J. Biol. Chem., 260:11554-11559 (1985) PA0 .sup.20 Brewer, et al., J. Neurosci. Res., 35(5)567-576 (1993) PA0 .sup.21 Seubert, et al., Nature, 359:325-327 (1992) PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-phenyl-5-pyraz olone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclohexyl-5-p yrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclobutyl-5-p yrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclopentyl-5- pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cycloheptyl-5- pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-benzyl-5-pyraz olone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-t-butyl-5-pyra zolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(4-heptyl)-5-p yrazolone PA0 3-(5-methoxy-2-methyl-3-indolylmethyl)-1-cyclohexyl-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-3-indolylmethyl]-1-cyclohexyl-5-pyrazolone PA0 3-(1-benzyl-5-methoxy-2-methyl-3-indolylmethyl)-1-cyclohexyl-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylethyl]-1-cyclohexyl-5-py razolone PA0 3-[1-(4-chlorobenzoyl)-2-methyl-3-indolylmethyl]-1-cyclohexyl-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(4-methoxyphen yl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-methoxyphen yl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-trifluorome thylphenyl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-chloropheny l)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3,5-dichlorop henyl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-bromophenyl )-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3,5-dimethylp henyl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-nitrophenyl )-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-methylpheny l)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-fluoropheny l)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3,4-dichlorop henyl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(4-methylpheny l)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-methyl-6-py ridazinyl)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(2-quinoxaliny l)-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(4-trifluorome thylphenyl)-5-pyrazolone PA0 3-[1-(3,4-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclohexyl -5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-aminophenyl )-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-acetamidoph enyl)-5-pyrazolone PA0 3-[1-(4-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclohexyl-4 -methyl-5-pyrazolone PA0 3-[1-(4-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclohexyl-4 ,4-dimethyl-5-pyrazolone PA0 3-[1-(4-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-cyclohexyl-4 -benzylidene-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-methyl-5-pyraz olone PA0 3-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3,4-dimethylp henyl)-5-pyrazolone PA0 3-(3-indolylmethyl)-1-cyclohexyl-5-pyrazolone PA0 3-(3-indolyl-n-propyl)-1-cyclohexyl-5-pyrazolone PA0 3-[1-(4-chlorobenzoyl)-3-indolylmethyl]-5-pyrazolone PA0 3-[1-(benzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-trifluoromethyl)-5- pyrazolone PA0 3-[1-(4-methoxybenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-trifluorom ethyl)-5-pyrazolone PA0 3-[1-(2-naphthoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-trifluoromethyl )-5-pyrazolone PA0 3-[1-(4-cyanobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl]-1-(3-trifluoromet hylphenyl)-5-pyrazolone PA0 3-[1-benzyl-2-methyl-3-indolylmethyl]-1-cyclohexyl-5-pyrazolone PA0 3-[1-phenyl-2-methyl-3-indolylmethyl]-1-cyclohexyl-5-pyrazolone PA0 3-[3-indolylethyl]-1-cyclohexyl-5-pyrazolone PA0 ethyl 4-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-3-oxobutyrate PA0 ethyl 4-(5-methoxy-2-methyl-3-indolyl)-3-oxobutyrate PA0 ethyl 4-(3-indolyl)-3-oxobutyrate PA0 ethyl 4-[1-(4-chlorobenzoyl)-3-indolyl]-3-oxobutyrate PA0 ethyl 4-(1-benzyl-5-methoxy-2-methyl-3-indolyl)-3-oxobutyrate. PA0 ethyl 4-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-3-oxopentanoate PA0 ethyl 4-[1-(4-chlorobenzoyl)-2-methyl-3-indolyl]-3-oxobutyrate PA0 ethyl 4-[1-(3,4-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-3-oxobutyrate PA0 ethyl 4-[1-(4-chlorophenyl)-5-methoxy-2-methyl-3-indolyl]-2-methyl-3-oxobutyrate PA0 methyl 4-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-3-oxobutyrate PA0 methyl 4-(5-methoxy-2-methyl-3-indolyl)-3-oxobutyrate PA0 n-butyl 4-[1-(4-chlorobenzoyl)-3-indolyl]-3-oxobutyrate PA0 n-hexyl 4-(1-benzyl-5-methoxy-2-methyl-3-indolyl)-3-oxobutyrate PA0 n-decyl 4-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-3-oxopentanoate PA0 n-heptyl 4-[1-(4-chlorobenzoyl)-2-methyl-3-indolyl]-3-oxobutyrate PA0 n-pentyl 4-[1-(3,4-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]-3-oxobutyrate PA0 t-butyl 4-[1-(4-chlorophenyl)-5-methoxy-2-methyl-3-indolyl]-2-methyl-3-oxobutyrate
All of the above publications, patent applications and patents are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or patent was specifically and individually indicated to be incorporated by reference in its entirety.